In a randomized, multinational phase 3 study (ALPINE), Jennifer Brown, MD, of the Dana-Farber Cancer Institute, and colleagues compared the results of zanubrutinib treatment versus ibrutinib on progression-free survival (PFS), overall response rate (ORR), and safety/tolerability profile in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic leukemia (R/R CLL/SLL). Data from the three-year follow-up results were presented at the 2023 ASH Annual Meeting & Exposition.

Dr Brown and colleagues adopted a comparative approach to discern the effectiveness and safety of zanubrutinib and ibrutinib in patients with R/R CLL/SLL. Participants who had previously received at least one prior therapy and experienced significant disease progression were eligible for this study. The selected patients were randomized on a 1:1 basis to receive either zanubrutinib or ibrutinib. The efficacy assessment of progression-free survival (PFS) and overall response rate (ORR) were determined in accordance with 2008 iwCLL criteria. To validate the results obtained from PFS, sensitivity analyses were also implemented. Updated safety analyses were performed throughout the study. However, it is important to note that all reported P-values are strictly descriptive.

This study involved 652 patients who were evenly split and randomized to receive either zanubrutinib (327 patients) or ibrutinib (325 patients). At a median follow-up time of 40.3 months for zanubrutinib and 38.7 months for ibrutinib, the study demonstrated a sustained benefit of zanubrutinib over ibrutinib on PFS and ORR. The PFS rates at the 36-month mark stood at 64.9% for zanubrutinib and 54.8% for ibrutinib. This benefit was also recorded across significant subgroups, namely in patients with del(17p)/TP53 mutations, with respective PFS rates of 58.6% and 41.3% at the 36-month mark. In terms of response, the ORR was slightly higher with zanubrutinib at 89.9% when compared to ibrutinib’s at 36 months. 

Adverse events (AEs) and progressive disease (PD) were the leading causes for treatment discontinuation in both study groups. Specifically, AEs led to discontinuation in 19.8% of the zanubrutinib group and 26.2% of the ibrutinib group. Comparable percentages were seen in discontinuation due to PD (39.2% for zanubrutinib and 36.0% for ibrutinib). Analyzing dose modifications, both treatments had similar rates of dose interruption and dose reduction due to AEs. Adverse effects were recorded in both groups, with the most common being COVID-19, neutropenia, and hypertension. Any grade ≥3 AEs and serious AEs were slightly higher in the ibrutinib group at 77.5% and 72.5%. Zanubrutinib had slightly less cardiac adverse events then ibrutinib (24.7% vs 34.6%). Overall, zanubrutinib demonstrated a better cardiac safety profile, substantiated by lower rates of cardiac events, such as atrial fibrillation/flutter, compared to ibrutinib. 

Dr Brown and her colleagues successfully established the superiority of zanubrutinib over ibrutinib in terms of PFS in a direct comparison of BTK inhibitors in the ALPINE study. The stability of these benefits over a median follow-up period of three years reveals zanubrutinib’s significant potential, further corroborated by its consistent performance across distinct subgroups and sensitivity analyses. This study documents zanubrutinib’s safety and tolerability throughout the study period, with its cardiac safety profile proving advantageous over that of ibrutinib, marking its continued potency as a treatment for patients with R/R CLL/SLL even after more than three years of treatment. Ongoing follow-up data will serve to reconfirm and consolidate the findings.

Brown JR, Eichhorst BF, Lamanna N, et al. Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL). Presented at: the 2023 ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA, and virtual; Abstract 202.